els

-Ra

8, 16

International Journal of Infectious Diseases 16 (2012) e735e738

Contents lists available at SciVerse ScienceDirect

International Journal of Infect

. co1. Introduction

In the adult population, acute tonsillopharyngitis accounts for12% of all visits to outpatient clinics, physician ofces, andemergency departments.1 Approximately 517% of acute tonsillo-pharyngitis cases are due to a bacterial infection, often to group Ab-hemolytic streptococci (GAS).2,3 The recurrence of clinicaltonsillopharyngitis in adults represents a medical problem aswell as an economic burden. Several factors have been consideredto explain the recurrence of tonsillopharyngitis. These include lowpatient compliance, short duration of antibiotic treatment, lowabsorption of antibiotic, frequent exposure (family/peers), bacte-rial tolerance, and other unknown reasons.413

The association between vitamin D deciency and thesusceptibility to infections of the respiratory tract has been

suggested for many years. Children with nutritional rickets havedeveloped rachitic lung due to infections of the respiratorytract.14 Recently, epidemiological studies have demonstrated acorrelation between vitamin D concentration and the incidenceof respiratory infections.1518 Moreover, scientic evidenceshows the important role of vitamin D in the immunesystem.19,20 The antimicrobial peptides (AMPs) defensin andcathelicidin, which are the principal defense factors of the upperrespiratory tract (URT), are upregulated by vitamin D.21,22 Aydinet al. showed that vitamin D insufciency was more prevalent inchildren with recurrent tonsillitis than in healthy children.23

Despite the fact that such an association between vitamin Ddeciency and the susceptibility to infections of the respiratorytract has been suggested for many years, to the best of ourknowledge no such evidence-based study had been undertakenin adults.

In this study we aimed to look for a possible associationbetween serum 25-hydroxy (25(OH)) vitamin D levels andrecurrent GAS tonsillopharyngitis in adults.

A R T I C L E I N F O

Article history:

Received 23 December 2011

Accepted 11 May 2012

Corresponding Editor: William Cameron,Ottawa, Canada

Keywords:

Recurrent tonsillopharyngitis

Group A Streptococcus

Vitamin D

Adults

S U M M A R Y

Objectives: To determine the association between recurrent group A streptococcal (GAS) tonsillophar-

yngitis and serum 25-hydroxy (25(OH)) vitamin D among adult subjects.

Methods: Adult patients with tonsillopharyngitis between January 2007 and December 2009 were

reviewed and identied retrospectively. Cases with a medical history of recurrent GAS tonsillophar-

yngitis were compared to age- and gender-matched individuals without a medical history of GAS

tonsillopharyngitis. Recurrent tonsillopharyngitis was dened as three or more episodes of GAS

tonsillopharyngitis per year for a period of two consecutive years.

Results: Fifty-four cases with recurrent GAS tonsillopharyngitis and 50 controls were enrolled. There

were no signicant differences between cases and controls with regard to mean age (41 13 vs. 42 12years; p = 0.7) and male gender (55% vs. 54%; p = 0.6). Mean serum levels of 25(OH) vitamin D among subjects

with recurrent GAS tonsillopharyngitis were signicantly lower from the controls (11.5 ng/ml 4.7 vs. 26ng/ml 7; p = 0.001). Multiple regression analysis showed that a serum 25(OH) vitamin D level

2. Materials and methods

2.1. Subjects

This study included adult patients with recurrent tonsillophar-yngitis who were followed-up at the Infectious Diseases Unit of theHoly Family Hospital (HFH), a 150-bed primary care hospital inNazareth, Israel. We included all individuals with recurrenttonsillopharyngitis who were followed-up between 2007 and 2009and who were aged 1860 years. The exclusion criteria were: (1) non-GAS tonsillopharyngitis, (2) pregnancy, and (3) individuals with:renal failure (creatinine clearance rate 30 kg/m2. For laboratory tests,levels considered normal were: CRP 00.5 mg/l, serum iron 60180 mg/dl, serum creatinine 0.671.17 mg/dl, and serum calcium

ic

W. Nseir et al. / International Journal of Infectious Diseases 16 (2012) e735e738e736therapy, vitamin D supplementation, and substance abusers.The control group included 50 healthy individuals without a

medical history of GAS tonsillopharyngitis who were enrolledrandomly from the Medicine Clinic, HFH. The members of thisgroup were matched with the study patients for age 4 years andgender, and were subject to the same exclusion criteria as the studypatient group. For each case of recurrent GAS tonsillopharyngitis weselected one comparator case (1:1). The study was reviewed andapproved by the local ethics committee of the FHF, Nazareth.

2.2. Study design

A retrospective study was carried out to examine theassociation between serum 25(OH) vitamin D levels and recurrentGAS tonsillopharyngitis in adults. The following were comparedbetween the groups of subjects with and without GAS tonsillo-pharyngitis: age, gender, body mass index (BMI), serum iron, C-reactive protein (CRP), diabetes mellitus, and serum levels of25(OH) vitamin D.

Information concerning medical conditions, drug therapy, andthe results of laboratory tests were extracted from the medicalcharts of each subject in both groups. (In general, every patientwho visits the Infectious Diseases Unit or Medicine Cliniccompletes a standard questionnaire at every visit concerninghis/her medical condition, anthropometric information, dietaryhabits, smoking, drug therapy, family history of different diseases,and systemic bacterial infections.)

2.3. Sampling and measures

Laboratory tests were performed within 4 days from thebeginning of the tonsillopharyngitis symptoms and includedserum CRP levels, creatinine, serum calcium, and serum iron,and a complete blood count. Serum 25(OH) vitamin D levels weremeasured in the winter and summer seasons (twice a year) for all

Table 1Demographic clinical, and some clinical laboratory data, cases vs. controls

Characteristic Cases (n = 54)

Agea (years) 41 13 Male sex 30 (55%)

BMIa (kg/m2) 27 4.4 Diabetes mellitus 7 (13%)

Creatininea (mg/dl) 0.7 0.15 Serum CRPa (mg/l) 4.9 3.3 Serum 25(OH) vitamin Da (ng/ml) 11.5 4.7 Serum 25(OH) vitamin D

W. Nseir et al. / International Journal of Infectious Diseases 16 (2012) e735e738 e737The most clear differences were seen in the mean levels ofserum CRP and 25(OH) vitamin D. Univariate analysis showed asignicant association between male gender, CRP, and serum25(OH) vitamin D. Table 2 shows the results of the multiple logisticregression analysis for identifying risk factors for recurrent GAStonsillopharyngitis after adjusting for the confounders of BMI,diabetes mellitus, serum iron levels, serum creatinine, and serumcalcium. The analysis showed that serum CRP >3 mg/l and serum25(OH) vitamin D 3 mg/l 1.57 (1.132.19) 0.007

Serum 25(OH) vitamin D 3 mg/l were found to be associated withrecurrent tonsillopharyngitis. The CRP value is usually elevated inpatients with GAS tonsillopharyngitis and the CRP test has alsobeen shown to be useful in differentiating GAS tonsillopharyngitisfrom other kinds of throat infection.4244Melbye et al. showed thata periodic CRP measurement is an effective tool for monitoringpatients with GAS tonsillopharyngitis during antibiotic therapy.45Previous studies have demonstrated that iron deciency isprevalent in children with recurrent tonsillitis and in childrenundergoing adenotonsillectomy.46,47 Low serum iron levels havebeen associated with abnormalities in the cell-mediated responseas well as a decreased ability of phagocytic cells to kill certain typesof bacteria.48 Elverland et al. showed a benecial effect oftonsillectomy and adenoidectomy on hemoglobin and ironmetabolism and found that iron deciency was common amongchildren with recurrent tonsillitis and upper airway obstruction.49

In our study, we did not nd any correlation between serum ironlevels and recurrent tonsillopharyngitis in adults.

We conclude that recurrent GAS tonsillopharyngitis in adultscould be related to vitamin D levels. Data from epidemiologicalstudies indicate that vitamin D deciency has become a commonnding in recent years and appropriate replacement may offerimmune and antimicrobial benets. Because measurement ofvitamin D levels is easily done and vitamin D supplements arereadily obtainable and inexpensive, further studies are needed toassess whether this represents a causal association and whethervitamin D replacement therapy can prevent the recurrence of GAStonsillopharyngitis.

Conict of interest: No conict of interest to declare.

References

1. Schappert SM. Ambulatory care visits to physician ofces, hospital outpatientdepartments, and emergency departments: United States, 1996. Vital HealthStat 1998;13(134):137.

2. Houvinen P, Lahtonen R, Ziegler T, Meurman O, Hakkarainen K, Miettinen A,et al. Pharyngitis in adults: the presence and coexistence of viruses and bacterialorganisms. Ann Intern Med 1989;110:6126.

3. Komaroff AL, Pass TM, Aronson MD, Ervin CT, Cretin S, Winickoff RN, et al. Theprediction of streptococcal pharyngitis in adults. J Gen Intern Med 1986;1:17.

4. Eisen SA, Miller DK, Woodward RS, Spitznagel E, Przybeck TR. The effect ofprescribed daily dose frequency on patient medication compliance. Arch InternMed 1990;150:18814.

5. Breese BB, Disney FA, Talpey WB. Penicillin in streptococcal infections: totaldose and frequency of administration. Am J Dis Child 1965;110:12530.

6. Khajavi A, Amirhakimi GH. The rachitic lung. Pulmonary ndings in 30 infantsand children with malnutritional rickets. Clin Pediatr 1977;16:368.

7. el-Daher NT, Hijazi SS, Rawashdeh NM, al-Khalil IA, Abu-Ektaish FM, Abdel-LatifDI. Immediate vs. delayed treatment of group A beta-hemolytic streptococcalpharyngitis with penicillin V. Pediatr Infect Dis J 1991;10:12630.

8. Pichichero ME, Disney FA, Talpey WB, Green JL, Francis AB, Roghmann KJ, et al.Adverse and benecial effects of immediate treatment of group A beta-hemo-lytic streptococcal pharyngitis with penicillin. Pediatric Infect Dis J 1987;6:63543.

9. Gerber MA, Randolph MF, Demeo KK, Kaplan EL. Lack of impact of earlyantibiotic therapy for streptococcal pharyngitis on recurrence rates. J Pediatr1990;117:8538.

10. Pichichero ME, Casey JR. Systemic review of factors contributing to penicillintreatment failure in Streptococcus pyogenes pharyngitis. Otolaryngol Head NeckSurg 2007;137:8517.

11. Kim KS, Kaplan EL. Association of penicillin tolerance with failure to eradicategroup A streptococci from patients with pharyngitis. J Pediatr 1985;107:6814.

12. Grahn E, Holm SE, Roos K. Penicillin tolerance in beta-streptococci isolated frompatients with tonsillitis. Scand J Infect Dis 1987;19:4216.

13. Dagan R, Ferne M, Sheinis M, Alkan M, Katzenelson E. An epidemic of penicillin-tolerant group A streptococcal pharyngitis in children living in closed commu-nity: mass treatment with erythromycin. J Infect Dis 1987;156:5146.

14. Najada AS, Habashneh MS, Khader M. The frequency of nutritional ricketsamong hospitalized infants and its relation to respiratory diseases. J Trop Pediatr2004;50:3648.

15. Sabetta JR, DePetrillo P, Cipriani RJ, Smardin J, Burns LA, Landry ML. Serum 25-hydroxyvitamin D and the incidence of acute viral respiratory tract infections inhealthy adults. PLoS One 2010;14:1108.

16. Berry DJ, Hesketh K, Power C, Hypponen E. Vitamin D status has a linearassociation with seasonal infections and lung function in British adults. Br JNutr 2011;106:143340.

17. Grant WB. Variation in vitamin D production could possibly explain theseasonality of childhood respiratory infections in Hawaii. Pediatr Infect Dis J2008;27:853.

18. Ginde AA, Mansbach JM, Camargo Jr CA. Association between serum 25-hydroxyvitamin D level and upper respiratory tract infection in the ThirdNational Health and Nutrition Examination Survey. Arch Intern Med 2009;169:38490.

19. Diamond G, Legarda D, Ryan LK. The innate immune response of the respiratoryepithelium. Immunol Rev 2000;173:2398402.

20. Medzhitov R, Janeway Jr C. Innate immune recognition: mechanisms andpathways. Immunol Rev 2000;173:8997.

21. Brogden KA. Antimicrobial peptides: pore formers or metabolic inhibitors inbacteria? Nat Rev Microbiol 2005;3:23850.

22. Liu PT, Stenger S, Li H, Wenzel L, Tan BH, Krutzik SR, et al. Toll-like receptortriggering of a vitamin D-mediated human antimicrobial response. Science2006;311:17703.

23. Aydin S, Aslan I, Yildiz I, Agachan B, Toptas B, Toprak S, et al. Vitamin D levels inchildren with recurrent tonsillitis. Int J Pediatr Otorhinolaryngol 2011;75:3647.

24. Bisno AL, Gerber MA, Gwaltney Jr JM, Kaplan EL, Schwartz RH. Practice guide-lines for the diagnosis and management of group A streptococcal pharyngitis.Clin Infect Dis 2002;35:11325.

25. Holick MF. Vitamin D deciency. N Engl J Med 2007;357:26681.26. Arnson Y, Amital H, Shoenfeld Y. Vitamin D and autoimmunity: new etiological

and therapeutic consideration. Ann Rheum Dis 2007;66:113742.27. Adams JS, Hewison M. Update in vitamin D. J Clin Endocrinol Metab 2010;95:

4718.28. Nnoaham KE, Clarke A. Low serum vitamin D levels and tuberculosis: a systemic

review and meta-analysis. Int J Epidemiol 2008;37:1139.29. Laaksi I, Ruohola JP, Touhimaa P, Auvinen A, Haataja R, Pihlajamaki H, et al. An

association of serum vitamin D concentration < 40 nmol/L with acute respira-tory tract infection in young Finnish men. Am J Clin Nutr 2007;86:7147.

30. Nseir W, Taha H, Khateeb J, Grosovski M, Assy N. Fatty liver is associated withrecurrent bacterial infections independent of metabolic syndrome. Dig Dis Sci2011;56:332834.

31. Urashima M, Segawa T, Okazaki M, Kurihara M, Wada Y, Ida H. Randomized trialof vitamin D supplementation to prevent seasonal inuenza A in school-children. Am J Clin Nutr 2010;91:125560.

32. Laaksi I, Ruohola JP, Mattila V, Auvinen A, Ylikomi T, Pihlajamaki H. Vitamin Dsupplementation for the prevention of acute respiratory tract infection: arandomized double-blinded trial amongst young Finnish men. J Infect Dis2010;202:80914.

33. Li-Ng M, Aloia JF, Pollack S, Cunha BA, Mikhail M, Yeh J, et al. A randomizedcontrolled trial of vitamin D3 supplementation for the prevention of symp-tomatic upper respiratory tract infections. Epidemiol Infect 2009;137:1396404.

34. Wallis DE, Penckofer S, Sizemore GW. The sunshine decit and cardiovasculardisease. Circulation 2008;118:147685.

35. Giovannucci E, Liu Y, Hollis BW, Rimm EB. 25-Hydroxyvitamin D and risk ofmyocardial infarction in men. Arch Intern Med 2008;168:117480.

36. Bikle DD. Vitamin D and the immune system: role in protection againstbacterial infection. Curr Opin Nephrol Hypertens 2008;17:34852.

37. Gombart AF, Borregaard N, Koefer HP. Human cathelicidin antimicrobial peptide(CAMP)gene is a direct targetof the vitamin D receptor and is stronglyup-regulatedin myeloid cells by 1,25-dihydroxyvitamin D3. FASEB J 2005;19:106777.

38. Chromek M, Slamova Z, Bergman P, Kovacs L, Podracka L, Ehren I, et al. Theantimicrobial peptide cathelicidin protects the urinary tract against invasivebacterial infection. Nat Med 2006;12:63641.

39. Wang TT, Nestel FP, Bourdeau V, Nagai Y, Wang Q, Liao J, et al. Cutting edge:1,25-dihydroxyvitamin D3 is a direct inducer for antimicrobial peptide geneexpression. J Immunol 2004;173:290912.

40. Akbar NA, Zacharek MA. Vitamin D: immunomodulation of asthma, allergicrhinitis, and chronic rhinosinusitis. Curr Opin Otolaryngol Head Neck Surg 2011;19:2248.

41. Bartley J. Vitamin D, innate immunity and upper respiratory tract infections. JLaryngol Otol 2010;124:4659.

42. Kaplan EL, Wannamaker LW. C-reactive protein in streptococcal pharyngitis.Pediatrics 1977;60:2832.

43. Hjortdahl P, Melbye H. Does near-to-patient testing contribute to the diagnosisof streptococcal pharyngitis in adults? Scand J Prim Health Care 1994;12:706.

44. Gulich MS, Matschiner A, Gluck R, Zeitler HP. Improving diagnostic accuracy ofbacterial pharyngitis by near patient measurement of C-reactive protein (CRP).Br J Gen Pract 1999;49:11921.

45. Melbye H, Bjorkheim MK, Leinan T. Daily reduction in C-reactive protein values,symptoms, signs and temperature in group-A streptococcal pharyngitis treatedwith antibiotics. Scand J Clin Lab Invest 2002;62:5215.

46. Busuttil A, Kerr AI, Logan RW. Iron deciency in children undergoing adenoid-tonsillectomy. J Laryngol Otol 1979;93:4958.

47. Mira E, Benazzo M, Asti L, Marchi A, Spriano P, Losi R. Iron status in childrenundergoing tonsillectomy and its short-term modication following surgery.Acta Otolaryngol 1988;454:2614.

48. Dallman PR. Iron deciency and the immune response. Am J Clin Nutr 1987;46:32934.

49. Elverland HH, Aasand G, Miljeteig H, Ulvik RJ. Effects of tonsillectomy andadenoidectomy on hemoglobin and iron metabolism. Ind J Pediatr Otorhinolar-yngol 2004;68:41923.

W. Nseir et al. / International Journal of Infectious Diseases 16 (2012) e735e738e738

The association between vitamin D levels and recurrent group A streptococcal tonsillopharyngitis in adultsIntroductionMaterials and methodsSubjectsStudy designSampling and measuresDefinitionsStatistical analysis

ResultsDiscussionReferences